Changes in extracellular Ca2+ influence secretion of H+ by the gastric glands and of HC03- by the neighboring gastric surface epithelium. Recent work in our laboratory indicates that the recently cloned extracellular Ca2+ - sensing receptor (CaR) is localized to the basolateral membranes of gastric cells such as the acid-secreting parietal cells and the mucus/HCO3--secreting surface epithelium. The overall goal of the work proposed in this application is to understand the physiological role of CaR in regulating protective functions of the mucus/HCO3--secreting surface epithelial cells. We hypothesize: 1) that the CaR regulates secretion and pHi regulation in gastric surface cells; 2) that changes in extracellular Ca2+ concentration occur during physiological stimulation of secretion or during acute injury; and 3) that changes in extracellular pH (known to occur during activation of secretion or with back-diffusion of H+ to the gastric submucosa. These hypotheses will be addressed using in vitro preparations of surface epithelium of amphibian gastric mucosa and isolated surface cells from rat gastric mucosa Specific activators and inhibitors will be used to evaluate the effects of CaR on secretion, pHi regulation, and intracellular Ca2+, under control conditions and during stimulation with physiologic secretagogues or during conditions mimicking acute injury. These studies may lead to identification of a novel regulatory pathway of gastric physiologic responses and to better understanding of how CaR activity influences cells not directly involved in systemic Ca2+ homeostasis.